The increasing prevalence of Alzheimer's disease (AD) in our aging population poses a significant challenge to public health. Current AD drug therapies have modest efficacy for reducing the loss of recent memory, the most common early symptom of AD, but have minimal ability to modify the underlying neurodegeneration. Our long range goal is to develop a safe drug to treat both the early symptomatic loss of memory and to reduce the underlying neurodegeneration. While much effort has gone into the development of [unreadable]-secretase inhibitors, few drug strategies have focused on the a-secretases which cleave the transmembrane [unreadable] amyloid precursor protein (APP) to generate a nontoxic fragment, sAPPa, the soluble form of amyloid precursor protein. a-Secretase activity is known to be increased by activators of protein kinase C, including bryostatin, a macrolide lactone, that also enhances rat maze learning and rabbit nictitating membrane conditioning. Bryostatin has never been used to treat AD. As an anti-tumor agent, it shows minimal efficacy but also minimal human toxicity in doses < 30 [unreadable]g/m2/week. The central hypothesis is that intermittent administration of low doses of bryostatin will cause maximal activation of PKC isozymes a and e and MAP kinase Erk1/2 with minimal human toxicity. The rationale for this proposal is that cognitive enhancement and neuroprotection result from bryostatin's potent activation of PKC and long-term enhancement of MAP kinase Erk1/2 synthesis. To test this hypothesis and accomplish our objectives, we will pursue the following Specific Aims: 1) to measure the in vitro and in vivo biochemical effects of bryostatin-1 (and "bryologs") on membrane and cytosolic PKC isozymes and a-secretase(s) and to determine dosing regimens with minimal toxicity based on maximal PKC activation, a-secretase isozymes, and prolonged protein synthesis; 2) to assess cognitive enhancement of bryostatin and bryologs and their efficacy in vivo in young and aged normal rats; and 3) to determine cognitive enhancement with spatial maze testing and neuroprotective efficacy in vivo in AD transgenic mice 129S6.Cg-Tg(APPSWE)2576Kha with measurements of reduced neurodegeneration that include mortality, sAPP secretion, levels of A[unreadable]1-42, and A[unreadable]1-40, amyloid plaque burden and tau phosphorylation. This research will provide a foundation for planned clinical trials of bryostatin as a novel therapy to improve the symptoms of AD and potentially offer neuroprotection against this devastating disease. [unreadable] [unreadable] [unreadable]